TR2021018876A2 - TOFASITINIB FILM-COATED TABLET FORMULATIONS WITH IMPROVED DISSOLVING SPEED - Google Patents

Abstract

The present invention is tofacitinib film-coated tablet formulation and its feature is; It contains 1-15% by weight of tofacitinib citrate as active ingredient, 25-35% by weight of lactose monohydrate as a filler, microcrystalline cellulose 40-60% by weight as a diluent, 1-4% by weight of croscarmellose sodium as a dispersing agent and It is characterized by the use of the direct printing production method.

Description

DESCRIPTION TOFASITINIB FILM COATED WITH IMPROVED DISSOLVING SPEED TABLET FORMULATIONS Technical Area The present invention relates to the field of pharmaceutical technology and has an improved dissolution rate. Pharmaceutical formulations in the form of film-coated tablets containing the active ingredient tofacitinib and describes the production technology. Prior Art The active substance of tofacitinib was first published in Europe with the number EP123583OBI from Pfizer. described in the patent. Chemical name of Tofacitinib citrate salt 2-hydroxypropane-1,2,3- It is 1-yli-3-oxopropionnitrile. The chemical structure of Tofacitinib citrate salt is given below.

Tofacitinib is an oral Janus kinase (JAK) inhibitor. Today, tofacitinib with active ingredient drugs for rheumatoid arthritis (RA), psoriatic arthritis (PSA) and similar rheumatic diseases used in the treatment. Janus kinases (JAKs) are interferons on the cell membrane, cytokines or growth factors such as interleukins and erythropoietin intracellular that transmits signals arising from ligand-receptor interactions in the are enzymes.

According to the application forms of tofacitinib active substance, with traditional pharmaceutical applications Formulated as a mixture with compatible excipients. Tofacitinib citrate has high solubility, It is a low permeability and non-hygroscopic molecule. Active ingredient concentration Dissolution rate and final mixture content of the powder mixture at the level of 5% by weight uniformity results; highly dependent on optimized functional usage ranges and is considered risky. This optimization depends on the applied production process and the used belong to auxiliary materials. Pfizer is currently available in the form of 5 mg film-coated tablets. There is a product under the name Xeljanz belonging to the company. Dry as a production method for this product The granulation method was used.

The production method used in the preparation of the film-coated tablet dosage form depends on various factors. is selected accordingly. The most used production methods in the pharmaceutical industry; direct print, wet granulation, dry granulation and melt extrusion granulation. dry and wet The purpose of granulation is to improve the flow of the mixture or to increase its compressibility. Dry in production by granulation, without adding binder solution or granulation solution Since it produces granulation, the possibility of air pollution as a result of excessive dusting and high dust There is a high probability of cross-contamination. Low production capacity of dry granulation It also has disadvantages such as the need for storage space and excessive noise. One the other limiting factor is content uniformity; homogeneous even without content uniformity non-compounds with different amounts of active ingredient in each dosage form. can result. The production process with the wet granulation method is before the granules are printed. must necessarily include a drying step. While the drying process is economically costly, However, it is a very laborious process in terms of drying time and drying temperature. This viscosity, temperature, addition speed of the binder solution used in production, while affecting the structure and properties of the granule; drying time and humidity rate also affect the product quality. can affect. The melt extrusion granulation method is also important in terms of the production process. involves many steps and is costly.

In the tablet production method, the granulation processes applied before the production Although it is one of the most common techniques used in the formulation of Bringing the particle properties of the dust cluster to the closest possible required. Granulation to prevent heterogeneous particle size and dispersion. Keeping the process flow under control at every stage prolongs the process time and saves energy. causes losses. Sensitive to direct compression, heat, humidity and volatile It can prevent the problems of substances in dry and wet granulation.

As an element of the present invention, the formulation was prepared by the direct compression method. Direct compression application, moistening, heat and high pressure as in the wet granulation method does not require such actions. Moisture and heat applied in tableting in wet granulation are effective. not suitable for the stability of substances and the process in the preparation of tablets The fact that there are many steps indicates that the tablet features may vary from series to series. is increasing. With the direct printing method, using less equipment and less energy tablet production can be done in a shorter time compared to other methods. cost production and packaging with the direct printing method, which is a low and easy-to-apply method. durable, adequate hardness formulations are obtained. Also, granulation Impurity formation, which is a problem encountered in the method, causes a decrease in dissolution rates. is happening. With formulations prepared by direct compression method, stability tests are more with improved dissolution rate showing good disintegration time and dissolution profiles Tofacitinib film-coated tablet formulations were obtained.

The direct printing method is the most common choice because the production method is simple and economical. It is one of the tablet production methods. The direct printing method is the active ingredient entering the formulation. on the basis of mixing substances and auxiliary substances and bringing them directly into tablets. is based on. It is most suitable for heat, moisture sensitive substances and volatile substances. tablet preparation method. Excipients used in direct printing, desired flow and provides printability. The most commonly used fillers and diluents; Anhydrous lactose, lactose, sorbitol, mannitol, modified starches, microcrystalline cellulose. powdered cellulose, dibasic calcium phosphate, lactose monohydrate and calcium carbonate. filler in the present invention While lactose monohydrate was used as the diluent, microcrystalline cellulose was used.

In the experiments, lactose monohydrate and microcrystalline cellulose were used and other filling materials were used. Improved dissolution with a shorter dispersion time compared to solvents and diluents Film-coated tablet formulations with high speed were obtained.

Another auxiliary substance is dispersants. Distributors, disintegration of the tablet in the gastrointestinal tract and substances added to the formulation to facilitate the release of the drug. Example as corn and potato starch, croscarmellose sodium, sodium alginate, methyl cellulose and hydroxypropyl methyl cellulose can be given. Croscarmellose as dispersant in the present invention sodium is used. By adding roscarmellose sodium to the formulation, optimal dissolution Film-coated tablet products giving the result were obtained.

Lubricants as a lubricant, by showing anti-adhesion properties, reduce dust particles. to reduce the friction between is added for the purpose. Talc, magnesium stearate, stearic acid, hydrogenated vegetable oils, polyethylene gIIkOI and magnesium stearate are among the widely used lubricants. Available Magnesium stearate is used as the lubricant, which is the subject of the invention, and problems such as sticking of active substance particles to each other, which is an important problem. Tablet formulations with improved dissolution rate were obtained.

Below are the film-coated tablet formulations known in the art containing tofacitinib as an active ingredient. given. Considering the patents mentioned and products available on the market, the developed It is seen that there is a need for film-coated tablet formulations with dissolution speed.

E P2968155 B Pfizer patent 1 describes a pharmaceutical dosage taken once a day. form is described. In the patent, tofacitinib or its pharmaceutically equivalent salt and carrier A sustained-release tablet formulation prepared under favorable conditions of osmotic pressure containing is explained. Containing tofacitinib and cellulose derivative in the formulation core It is a sustained release dosage form containing a semipermeable membrane coated with a water-insoluble polymer.

The dosage form in question provides a primary release of tofacitinib by osmotic pressure. It is a tablet or capsule with an extrudable core system. Composition containing tofacitinib, Viscosifier polymers in varying amounts between 2 - 20% by weight and 60 - 85% by weight It contains osmotically active agents ranging from The resulting Tofacitinib tablet in its products; Up to 30% of tofacitinib dissolves in 1 hour, while more than 35% in 2.5 hours tofacitinib or a pharmaceutically acceptable salt thereof in the formulation described 2% to 20% polyethylene oxide (PEOl and hydroxyethyl cellulose (such as HECl) viscosifying polymers; Between 60% and 85% of osmotically active agents have been used.

Osmotically active agents include water-soluble salts such as sodium chloride, potassium chloride; lactose, sugars such as mannitol and sorbitol; organic acids such as ascorbic acid, benzoic acid and citric acid and low molecular weight organic compounds. In the patent in question, controlled Two-layer osmotic tablet formulations capable of releasing have been described. double layer Osmotic tablets are produced with a dual-phase production method and direct printing technology. couple here In the tablet indicated as phased, the active substance of tofacitinib citrate in the first layer, which is the active layer, polyethylene oxide and magnesium stearate; polyethylene oxide, sodium chloride, dye in the second layer substance and magnesium stearate were used. Coating content of cellulose acetate, hydroxypropyl Cellulose, acetone and pure water are available. Hydrophilic matrix controlled release tablet described in the patent In its formulations, the active ingredient of tofacitinib citrate is used at a rate of 7.1% by weight, Methocel polymer from hydroxypropyl methylcellulose derivatives to provide controlled release lactose monohydrate used as filler, 30% by weight It was used twice in the formulation. In the formulation examples given in the patent, It is explained that the production is made using the dry granulation method, Considering the examples given, formulations containing the active ingredient tofacitinib citrate The production of dry granulation requires both time and equipment and auxiliary materials. It seems more difficult to produce in terms of cost and problems in product stability is being made. Considering the patents mentioned and products available on the market, There is a need for film-coated tablet formulations with improved dissolution rates. is seen. The oldest and most commonly used drug release formulations of direct-release tablet formulations Although it is known that it has a mechanism of action, it is also the most effective drug release in terms of patient compliance. known. Therefore, in the present invention, direct-release tablet formulations It is produced by the printing method. In the present invention, the applied direct printing method is dry. the surface of the solid particles of the active substance and excipient compared to the granulation method more in terms of process reproducibility due to the fact that its specific properties do not change. It is an advantageous and less time-consuming production method. By direct printing method targeted, improved particulate flow, optimized excipient concentration, mixture uniformity, and dissolution rate profile similar to the reference product product is obtained. Dissolution of tablet formulations currently available in the market to increase the dissolution in the profile, at the same time, the core tablet experienced during printing formulations known in the prior art to prevent matting and breaking on the surface. Instead, innovative formulations are needed. In this context, the direct printing method In our present invention, which is prepared by using the film coating process, both the product its stability has been increased and its protection from moisture has been realized. Surprisingly, as a result of our studies, the active substance prepared by the direct printing method and 1-15% by weight tofacitinib Citrate, 25-35% by weight as filler lactose monohydrate, 40-60% by weight as diluent microcrystalline cellulose, containing 1 - 4% by weight croscarmellose sodium as a dispersant formulations and tofacitinib film-coated tablet products with the most suitable dissolution profile. has been found to be obtained.

Detailed description of the invention The present invention is a film-coated tablet formulation of tofacitinib, and its feature is; as active ingredient 1-15% by weight tofacitinib citrate, 25-35% by weight as filler Containing 1-4% croscarmellose sodium by weight as a dispersant and direct compression characterized by the use of the production method.

The examples given in Table 1 are given to illustrate the present invention in detail, but The scope of the invention is not limited to these examples.

The active substance of the formulation of tofacitinib 5 mg film-coated tablets according to the present invention and The amounts of excipients are given in Table 1. As the production method of the formulation Direct printing method was used.

Table 1. Tofacitinib 5 mg film-coated tablet formulations according to the invention Components Unit formula (% } Active substance Example 1 Tofacitinib citrate 1% to 15% Excipients Lactose monohydrate 25 - 35% Microcrystalline Cellulose % 40 - 60 Croscarmellose sodium 1% - 4% Magnesium stearate 0.5 - 2.5% Opadry White 2 -5 % Pure Water y.m.

Production used in the preparation of the film-coated tablet formulation according to the present invention method includes the following steps; l. Tofacitinib Citrate, microcrystalline cellulose, lactose monohydrate and croscarmellose sodium It is sieved together and mixed homogeneously. 2. Magnesium stearate is added to the prepared bulk and mixed. 3. The powder mixture prepared is printed on the tablet printing machine in accordance with the specifications. 4. The printed tablets are coated in the film coating machine in accordance with the specifications. Unlike Example 1, the amount of filler and diluent in the formulation is different. used in the range. The ratio of lactose monohydrate as a filler is 10 - 20%, diluent In Example 2 formulations developed as a microcrystalline cellulose ratio of 60 - 90 % The direct printing production method was used as the production method. Filling material in Table 2. and diluent amounts Tofacitinib 5 mg film-coated tablet used different from Example 1. formulations are given.

Table 2. Amounts of filler and diluent. Tofacitinib 5 mg film-coated tablet formulation Components Unit formula (%] Active substance Example 1 Tofacitinib citrate 1% to 15% Excipients Lactose monohydrate 10 - 20% Microcrystalline Cellulose 60 - 90 % Croscarmellose sodium 1% - 4% Magnesium stearate 0.5% , 2.5 Opadry White 2 -5 % Pure Water y.m. Unlike Example 1, the diluent and dispersant amounts were changed. As a diluent microcrystalline cellulose 60 - 90% and croscarmellose sodium 4 - 9% as dispersant Direct printing production as a production method in Example 3 formulations developed as method has been used. In Table 3, the diluent and dispersant amounts are different from Example 1.7. Tofacitinib 5 mg film-coated tablet formulations used were given.

Table 3. Amounts of diluent and dispersant Tofacitinib 5 mg used different from Example l Components Unit formula (%] Active substance Example 1 Tofacitinib citrate 1% to 15% Excipients Lactose monohydrate 25 - 35% Microcrystalline Cellulose 60 - 90 % Croscarmellose sodium 4 - 9% Magnesium stearate 0.5 - 2.5% Opadry White 2 - 5 % Pure Water y.m. Different from Example 1, different ratios of filler, diluent and dispersant in the formulation used. Iactose monohydrate 10-20% as a filler, as a diluent microcrystalline cellulose 60-90% and croscarmellose sodium 4-9% as dispersant Direct printing production as a production method in Example 4 formulations developed as method has been used. The amounts of filler, diluent and dispersant in Table 3 are from Example1. Tofacitinib 5 mg film-coated tablet formulations used differently were given.

Table 4. Amounts of filler, diluent and dispersant Used different from the example Tofacitinib 5 mg film-coated tablet formulation Components Unit formula (% l Active substance Example 1 Tofacitinib citrate 1% to 15% Excipients Lactose monohydrate 10 - 20% Microcrystalline Cellulose 60 - 90 % Croscarmellose sodium 4 - 9% Magnesium stearate 0.5% , 2.5 Opadry White 2 -5 % Pure Water y.m.

Dissolution analyzes of all samples developed as a result of the studies and fl-f2 analyzes were carried out. Dissolution analysis of the trial products and fl-f2 in Table 5. analysis results are given.

Table 5: Dissolution and fl-f2 analysis for Tofacitinib film-coated tablet formulation samples results Tofacitinib Citrate Dissolution % Examples pH 6.8 phosphate USP, 900 RPM, 100 ml. pedal *The dissolution specification in the European Pharmacopoeia is “at least % after 30 minutes” specified.

Difference Factor: It indicates the difference between the test product and the reference product.

Parameter calculated by the following method. denoted by fl: 1 Z ::IR' Similarity Factor: It indicates the similarity between the test product and the reference product.

The parameter calculated by the following method is denoted by f2: f2 : 50 logi 1+;Z:i(Ri _Tir In order to talk about the similarity between the dissolution rates of the two formulations, the value of fl should be 0; The f2 value should also be close to 100. Usually fl 's less than 15 (0-15] and f2's It is considered sufficient to be greater than 50 (50-100).

When dissolution analysis results and fl-I2 values are examined; best dissolution result It is seen that the formulations giving the values of and fl-f2 are Example 1 formulations. Although dissolution results were high in Example 2 formulation, fl-I2 values were appropriate. it didn't come out. Dissolution and f1-f2 results required specifications of Example 3 formulations However, it gave lower results compared to Example 1. Example 4 formulations 30 minutes, according to the criteria specified as the European Pharmacopoeia dissolution specification. did not meet the dissolution criteria of at least 80.0% at the end.

Claims (1)

REQUESTS 1. Tofacitinib is a film-coated tablet formulation, its feature is; 5 a] 1-15% by weight of tofacitinib citrate as active ingredient, b] 25-35% by weight of lactose monohydrate as filler, C] microcrystalline cellulose 40-60% by weight as diluent, d) % by weight as dispersant It is characterized by the fact that it contains croscarmellose sodium in the ratio of 1- 4 and the use of direct compression production method.